West Nile virus infection can cause severe debilitating consequences following productive infection. Severe encephalitis can result, which can lead to neurological dysfunction and death. There is no vaccine available, and only symptom-specific treatment following clinical evidence of infection. Immune responses to viral infections involve innate responses initially, which are followed by adaptive responses later. The innate response can modulate both viral clearance as well as pathogenesis of the virus. Indeed some viruses have developed sophisticated abilities to modulate the innate immune response, enhancing their infectivity. Innate responses are also induced following vaccination, due to the adjuvants utilized, and therefore, an understanding of these responses will allow for the development of appropriate vaccination strategies. There are virtually no reports available characterizing the innate immune response to West Nile virus. Therefore, in this revised exploratory R21 application we seek to define critical aspects of the host innate response to West Nile virus. We have chosen the R21 mechanism for several reasons. First, since little is known about the innate response to West Nile Virus, we will need to perform exploratory studies regarding the cell and receptors activated following infection. Secondly, the use of this flavivirus is new in our laboratory and we require support to be able to initiate studies on this important virus within our laboratory. Importantly we have arranged for a strategic collaboration between our laboratory and Dr. Margo Brinton, an established investigator in the West Nile virus field. This collaboration will be critical for our success in these West Nile virus investigations. We propose to test two hypotheses in this revised exploratory R21 application. Firstly, we will test the hypothesis that the NK repertoire is both activated and altered following infection by West Nile virus. Secondly, we will test the hypothesis that NK responses are required for viral clearance, but are also involved in viral pathogenesis. We believe that the information obtained from our studies will highlight the role of NK cells and their receptors in the host response to West Nile virus.